This invention relates to a novel synthetic procedure and, more particularly, to a novel method for the preparation of quinoxaline-di-N-oxides and related compounds such as benzimidazole-di-N-oxides and 1-hydroxybenzimidazole-3-oxides.
The compounds prepared by the novel subject process are useful in the control of various pathogenic microorganisms. Also, as shown in U.S. Pat. No. 3,047,579, such oxides are generally prepared by processes involving the direct oxidation of quinoxaline compounds and usually require the corresponding quinoxaline compound as the starting material. Oxidation reactions are generally known to be somewhat non-selective and may give rise to low yields of the desired product together with one or more difficult to separate by-products.
Landquist et al., J. Chem. Soc. 2052 (1956) reported the preparation of the ethyl ester and the amide of 3-methyl-2-quinoxalinecarboxylic acid-di-N-oxide in a search for compunds of improved antibacterial or antiprotozoal activity. However, no utility is alleged for either of these compounds.
Netherlands Specification 6,504,563, granted Oct. 18, 1965, reports the methyl ester of 2-quinoxalinecarboxylic acid-di-N-oxide and a series of N-substituted derivatives of 2-quinoxalinecarboxamide-di-N-oxide in which the substituent is an N,N-dialkylaminoalkyl group; e.g., N,N-dimethylaminoethyl-; N,N-diethylaminoethyl-; N,N-diethylaminopropyl-; N,N-dimethylaminoisobutyl-; and N,N-diethylamino-t-amyl; or a hydroxyalkyl group; e.g., 2-hydroxyethyl. The compounds are described as active agents against cancer. French Patent M3717, granted Jan. 3, 1966, generically discloses 2-quinoxalinecarboxamide-di-N-oxides in which the carboxamide group may be substituted with an alkyl, substituted alkyl, aryl, cycloalkyl, aralkyl, or cycloalkylalkyl group; or may form a heterocyclic amide, e.g., a piperidide. They are reported to be of use in human therapy as antitubercular, antibacterial, anticancer, antivirus and antiprotozoal agents.
Belgian Patent 697,976, granted Nov. 3, 1967, describes a variety of N-substituted derivatives of 3-methyl-2-quinoxalinecarboxamide-di-N-oxide in which the N-substituent is phenyl, substituted phenyl, dodecyl or ethyl. Also disclosed are cyclic amides, e.g., pyrrolidide and piperidide. They are said to be of value as intermediates for the preparation of vegetation protection agents and pharmaceutical agents and are prepared by the reaction of a benzofuroxan with a compound having a keto group adjacent to a methylene or methyl group in the presence of ammonia or a primary aliphatic amine.
Belgian Patent 721,724, published Apr. 2, 1969, describes a variety of N-substituted 3-methyl-2-quinoxalinecarboxamide-di-N-oxides wherein the N-substituent is alkyl, hydroxyalkyl, lower alkoxyalkyl, carbalkoxyalkyl, monoalkylaminoalkyl or di(alkyl)aminoalkyl groups as antibacterial agents.
Haddadin and Issidorides (Tetrahedron Letters, No. 36, 3253-6, 1965) reported the preparation of quinoxaline-di-N-oxides by the reaction of enamines with benzofuroxan (referred to therein as isobenzofuroxan).
The gram-negative antibacterial activity of several quinoxaline-di-N-oxides bearing 2-alkyl or 2,3-dialkyl groups has been described by Landquist et al., U.S. Pat. No. 2,626,259 issued Jan. 20, 1953, and by Wiedling, Acta Pathol et Microbiol, Scand. 22, 379-91 (1945), Mcllwain, J. Chem. Soc. 322 (1943) and King et al., J. Chem. Soc. 3012 (1949), disclose the antibacterial activity of 2-methyl-3-n-amylquinoxaline-di-N-oxide and of several 6-substituted quinoxaline-di-N-oxides, respectively. Hurst et al., Brit. J. Pharmacol. 8, 297 (1953) report on the antiviral properties of quinoxaline-di-N-oxide and various derivatives thereof against the largest viruses of the psittacosislymphogranuloma group. Hurst et al. report that few of the products were active against the virus (lymphogranuloma) in the chick embryo.